This invention relates to a novel method for the treatment or prevention of preferably non-insulin dependent (NIDDM or so-called Type II) diabetes mellitus, and in particular to the use of phytanic acid derivatives for the treatment or prevention of NIDDM.
NIDDM is the form of diabetes mellitus that occurs predominantly in adults in whom adequate production of insulin is available for use, yet a defect exists in insulin-mediated utilization and metabolism of glucose in peripheral tissues. Overt NIDDM is characterized by three major metabolic abnormalities: elevated serum glucose levels, resistance to insulin-mediated glucose disposal, and overproduction of glucose by the liver.
Previous mechanisms of action of oral antidiabetics such as the generally used sulfonyl ureas are primarily based on an increased release of insulin from the beta cells of the pancreas, a mechanism which in the long term may lead to accelerated exhaustion of the endogenous production of insulin in diabetics. The modern view of the pathobiochemistry of adult-onset diabetes mellitus therefore emphasizes the need to treat the peripheral insulin resistance that is present in this case.
The human diet contains phytol, a metabolite of the chlorophyll molecule. Phytol is metabolized to phytenic acid and phytanic acid (see FIG. 6). Intestinal absorption of phytol from dietary chlorophyll was shown to be minimal (Baxter, J. H. & Steinberg, D. (1967) Absorption of phytol from dietary chlorophyll in the rat, J Lipid Res. 8, 615–20; Baxter, J. H. (1968) Absorption of chlorophyll phytol in normal man and in patients with Refsum's disease, J Lipid Res. 9, 636–41).
In rats, phytol is much less well adsorbed than phytanic acid (Baxter, J. H., Steinberg, D., Mize, C. E. & Avigan, J. (1967) Absorption and metabolism of uniformly 14C-labeled phytol and phytanic acid by the intestine of the rat studied with thoracic duct cannulation, Biochim Biophys Acta. 137, 277–90).
In humans, dairy products and ruminant fats in-the human diet are the major sources of phytanic acid. A normal diet contains 50–100 mg of phytanic acid per day (Steinberg. (1995) Refsum Disease in the Metabolic and Molecular Bases of Inherited Metabolic Disorders pp. 2351–2369, McGraw-Hill, New York). Phytenic- and phytanic acid levels in normal human serum were 2 μM and 6 μM (Avigan, J. (1966) The presence of phytanic acid in normal human and animal plasma, Biochim Biophys Acta. 116, 391–4). Phytanic acid may be elevated 50-fold in patients with heredopathia atactica polyneuritiformis (Refsum's disease), an inherited metabolic disorder characterized by an α-hydroxylase gene defect that prevents the conversion of phytanic acid to pristanic acid (Verhoeven, N. M., Wanders, R. J., Poll-The, B. T., Saudubray, J. M. & Jakobs, C. (1998) The metabolism of phytanic acid and pristanic acid in man: a review, J Inherit Metab Dis. 21, 697–728).
In adult mice fed a 0.5% phytol diet for 21 days a 40% decrease in the triglyceride serum levels was noted. However, cholesterol serum levels remained unaffected (Van den Branden, C., Vamecq, J., Wybo, I. & Roels, F. (1986) Phytol and peroxisome proliferation, Pediatr Res. 20, 411–5). Moreover, expression of enzymes, known to be involved in beta-oxidation and regulated by peroxisome proliferator-activated receptor (PPAR) was observed to be up regulated. Recently it was shown that phytanic acid is a 9-cis-retinoic acid receptor (RXR) as well as a PPARα ligand (Kitareewan, S., Burka, L. T., Tomer, K. B., Parker, C. E., Deterding, L. J., Stevens, R. D., Forman, B. M., Mais, D. E., Heyman, R. A., McMorris, T. & Weinberger, C. (1996) Phytol metabolites are circulating dietary factors that activate the nuclear receptor RXR, Molecular Biology of the Cell. 7, 1153–66.; Lemotte, P. K., Keidel, S. & Apfel, C. M. (1996) Phytanic acid is a retinoid X receptor ligand, Eur J Biochem. 236, 328–33; Wolfrum, C., Ellinghaus, P., Fobkjer, M., Seedorf, U., Assmann, G., Borchers, T. & Spener, F. (1999) Phytanic acid is ligand and transcriptional activator of murine liver fatty acid binding protein, J Lipid Res. 40, 708–14.; Ellinghaus, P., Wolfrum, C., Assmann, G., Spener, F. & Seedorf, U. (1999) Phytanic acid activates the peroxisome proliferator-activated receptor alpha (PPARalpha) in sterol carrier protein 2-/sterol carrier protein x-deficient mice, J Biol Chem. 274, 2766–72 and WO 97/09039).
RXR receptor binding and transcriptional effects were observed with is EC50 and IC50 of 3 μM and 2.3 μM respectively. The Kd-value for phytanic acid as PPARα ligand is reported as 10 nM (Ellinghaus et al., supra). In contrast to the ability of 9-cis-retinoic acid to activate both RXR and all-trans-retinoic acid receptor (RAR) (EC50 2.5 nM and 13 nM), phytanic acid activity is restricted to RXR receptors. Activation of both PPARα and RXR by phytanic acid and the specificity with respect to the retinoid receptors may lead to a distinct pattern of gene induction as opposed to the pattern observed in other fatty acids.
Liver is second to skeletal muscle as the most important tissue in glucose metabolism and therefore is an important regulator of glucose level in plasma. It is well known that activation of PPARγ by the antidiabetic thiazolidinediones such as troglitazone rosiglitazone and pioglitazone leads to restored insulin sensitivity in case of diabetes mellitus type II (Berger, J., Bailey, P., Biswas, C., Cullinan, C. A., Doebber, T. W., Hayes, N. S., Saperstein, R., Smith, R. G. & Leibowitz, M. D. (1996) Thiazolidinediones produce a conformational change in peroxisomal proliferator-activated receptor-gamma: binding and activation correlate with antidiabetic actions in db/db mice, Endocrinology. 137, 4189–95; Lehmann, J. M., Moore, L. B., Smith-Oliver, T. A., Wilkison, W. O., Willson, T. M. & Kliewer, S. A. (1995) An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor gamma (PPARγ), J Biol Chem. 270, 12953–6.12, 13). Expression of PPARα as well as PPARγ was shown in liver of rodents and humans (Mukherjee, R., Jow, L., Croston, G. E. & Paterniti, J. R., Jr. (1997) Identification, characterization, and tissue distribution of human peroxisome proliferator-activated receptor (PPAR) isoforms PPARγ2 versus PPARγ1 and activation with retinoid X receptor agonists and antagonists, J Biol Chem. 272, 8071–6.; Lemberger, T., Braissant, O., Juge-Aubry, C., Keller, H., Saladin, R., Staels, B., Auwerx, J., Burger, A. G., Meier, C. A. & Wahli, W. (1996) PPAR tissue distribution and interactions with other hormone-signaling pathways, Ann N.Y. Acad Sci. 804, 231–51; Palmer, C. N., Hsu, M. H., Griffin, K. J., Raucy, J. L. & Johnson, E. F. (1998) Peroxisome proliferator activated receptor-alpha expression in human liver, Mol Pharmacol. 53, 14–22.; Vidal-Puig, A. J., Considine, R. V., Jimenez-Linan, M., Werman, A., Pories, W. J., Caro, J. F. & Flier, J. S. (1997) Peroxisome proliferator-activated receptor gene expression in human tissues. Effects of obesity, weight loss, and regulation by insulin and glucocorticoids, J Clin Invest. 99, 2416–22).
Phytanic acid was described as a ligand for both RXR and PPARα (Kitareewan, et al. (supra); Lemotte et al. (supra); Ellinghaus et al (supra) and WO 97/09039). Decaux et al. (Decaux, J. F., Juanes, M., Bossard, P. & Girard, J. (1997) Effects of triiodothyronine and retinoic acid on glucokinase gene expression in neonatal rat hepatocytes, Mol Cell Endocrinol. 130, 61–7) demonstrated in primary cultures of rat hepatocytes, an up-regulation of glucokinase mRNA by retinoic acid. Together with the finding that the phosphoenolpyruvate carboxykinase (PEPCK) gene is regulated among other responsive elements by a PPAR responsive element (PPRE) (Juge-Aubry, C., Pernin, A., Favez, T., Burger, A. G., Wahli, W., Meier, C. A. & Desvergne, B. (1997) DNA binding properties of peroxisome proliferator-activated receptor subtypes on various natural peroxisome proliferator response elements. Importance of the 5′-flanking region, J Biol Chem. 272, 25252–9; Hanson, R. W. & Reshef, L. (1997) Regulation of phosphoenolpyruvate carboxykinase (GTP) gene expression, Annu Rev Biochem. 66, 581–611), a RXR/PPAR mediated up-regulation of the glucose influx in hepatocytes could be a reasonable explanation. PPAR forms permissive heterodimers with RXR, meaning that either partner can regulate the transcriptional activity by interacting with its own ligand. Co-treatment of the cells with ligands for PPAR as well as RXR results in an additive effect. Moreover it was shown that ligands selective for RXR could activate PPRE driven reporter genes (Kliewer, S. A., Umesono, K., Noonan, D. J., Heyman, R. A. & Evans, R. M. (1992) Convergence of 9-cis retinoic acid and peroxisome proliferator signaling pathways through heterodimer formation of their receptors, Nature. 358, 771–4; Gearing, K. L., Gottlicher, M., Teboul, M., Widmark, E. & Gustafsson, J. A. (1993) Interaction of the peroxisome-proliferator-activated receptor and retinoid X receptor, Proc Natl Acad Sci U S A. 90, 1440–4; Keller, H., Dreyer, C., Medin, J., Mahfoudi, A., Ozato, K. & Wahli, W. (1993) Fatty acids and retinoids control lipid metabolism through activation of peroxisome proliferator-activated receptor-retinoid X receptor heterodimers, Proc Natl Acad Sci U S A. 90, 2160–4).
In vivo sensitization to insulin was observed in diabetic and obese mice in response to RXR agonists, comparable to the effects known from the thiazolidinediones (Mukherjee, R., Davies, P. J., Crombie, D. L., Bischoff, E. D., Cesario, R. M., Jow, L., Hamann, L. G., Boehm, M. F., Mondon, C. E., Nadzan, A. M., Paterniti, J. R., Jr. & Heyman, R. A. (1997) Sensitization of diabetic and obese mice to insulin by retinoid X receptor agonists, Nature. 386, 407–10).
However, there is no indication in the prior art that phytanic acid derivatives, preferably phytanic acid, would have a beneficial effect on NIDDM itself.